title: Indole-3-carbinol enhances oxidative stress responses resulting in the induction of preneoplastic liver cell lesions in partially hepatectomized rats initiated with diethylnitrosamine.
abstract: The liver tumor-promoting effects of indole-3-carbinol (I3C), a cytochrome P450 (CYP) 1A inducer found in cruciferous vegetables, were investigated using a medium-term hepatocarcinogenesis model in rats. Six-week-old male F344 rats received an intraperitoneal injection of N-diethylnitrosamine (DEN) and were fed a diet containing 0 (DEN-alone), 0.25, 0.50 or 1.0% of I3C for 8 weeks from 2 weeks after DEN-initiation. The number and area of liver cell foci positive for glutathione S-transferase placental form (GST-P) significantly increased in the livers of rats given 0.5% I3C or more, compared to those in the DEN-alone group. The number of GST-P positive foci also increased in the 0.25% I3C group. The number of liver cells positive for proliferating cell nuclear antigen (PCNA) significantly increased in all I3C groups compared to that in the DEN-alone group. Real-time RT-PCR analysis showed that I3C increased transcript levels of not only Cyp1a1 but also aryl hydrocarbon receptor (AhR) and/or nuclear factor (erythroid-derived 2)-like 2 (Nrf2) gene batteries, such as Cyp1a2, Cyp1b1, Ugt1a6, Nrf2, Nqo1, Gsta5, Gstm2, Ggt1and Gpx2. Reactive oxygen species (ROS) in the microsomal fraction significantly increased in all I3C-treated groups compared to the DEN-alone group, and thiobarbituric acid-reactive substances (TBARS) levels and 8-hydroxy-2'-deoxyguanosine (8-OHdG) content significantly increased in all of the I3C-treated groups and 1.0% I3C group, respectively. These results suggest that I3C is an AhR activator and enhances microsomal ROS production resulting in the upregulation of Nrf2 gene batteries, but the oxidative stress generated overcomes the antioxidant effect of Nrf2-related genes. Such 'a redox imbalance' subsequently induces liver tumor-promoting effects by enhancing cellular proliferation in rats.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Dewa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kemmochi
authors.forename: Eriko
authors.initials: E
authors.lastname: Taniai
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Masako
authors.initials: M
authors.lastname: Imaoka
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kuwata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004052:Diethylnitrosamine / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006498:Hepatectomy; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008297:Male; D046228:Microarray Analysis; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D002273:Carcinogens; D018076:DNA, Complementary; D016166:Free Radical Scavengers; D007211:Indoles; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D004052:Diethylnitrosamine; D000080242:8-Hydroxy-2'-Deoxyguanosine; C016517:indole-3-carbinol; D003849:Deoxyguanosine